Cell and biology-based therapies designed to promote myocardial recovery after injury or prevent progression of heart failure are being developed and tested in clinical trials. However a major limitation to work in this area is the relatively poor understanding of the cell biology of the human myocardium. Improving our understanding of the biology of cardiac progenitor cells function is the focus of this proposal. A small fraction of cells isolated from the adult human ventricular myocardium are highly proliferative in culture, and express key pluripotency transcription factors, and can be stimulated to differentiate into endothelial, cardiac myocyte, and mesenchymal lineages. These cells express CD105 (a.k.a. endoglin), which functions in the transmission of transforming growth factor beta (TGF?) and bone morphogenetic protein (BMP) signaling. These cells also express variable levels of ERBB1-4 receptor tyrosine kinases which mediate the effects of the epidermal growth factor (EGF) family including Neuregulin-1? (NRG). NRG and ERBB1-4 are critical for cardiac development and maintenance of the adult heart. The expression of ERBB1-4 in freshly isolated progenitor cells varies amongst individuals and is correlated to the quantity of highly proliferative clones that can be derived from myocardial biopsies. ERBB2 expression determines whether these progenitor cells can be induced toward an endothelial phenotype in response to stimulation with recombinant EGF or NRG-1. The co- expression of the BMP family co-receptor CD105, and its roles in angiogenesis and heart development, suggest co-regulation of these cells by this family of ligands. The central hypothesis of this proposal is that ERBB1-4 receptor expression is determined by BMP9/CD105 and regulates the viability, number, and ability of progenitor cells to differentiate to endothelial and other lineages. A collection of early passage progenitor cell clones isolated from ventricular myocardium in consenting subjects at Maine Medical Center has been created over the past 3 years. The functional significance of variable ERBB2 expression in these cells will be examined in the setting of cell transplant into mouse heart early and late after myocardial infarction in AIM 1. The mechanism by which BMP9/CD105/Alk1 regulates ERBB expression and its functional significance will be examined in AIM 2. Highly proliferative clones with similar characteristics can be isolated from skeletal muscle as well as atrial myocardium. The extent to which progenitor cells isolated from atrial myocardium and skeletal muscle are similar to the ventricular myocardium will be examined in AIM 3. Ultimately these findings will improve our understanding of how ERBB and CD105 regulate cardiovascular health as well as recovery from injury, and will inform the design of clinical strategies to enhance the restorative potential of the heart.